Neublastin, also known as artemin and enovin, is a 24 kDa homodimeric, secreted protein that promotes the outgrowth and survival of neurons of the peripheral and central nervous system (Baudet et al., 2000, Development, 127:4335; Masure et al., 1999, Eur. J. Biochem., 266:892; Rosenblad et al., 2000, Mol. Cell Neurosci., 15(2):199). Neublastin mRNA is expressed predominantly in embryonic kidney and lung, and in adults, is expressed highest in pituitary gland, trachea, and placenta (Baudet et al., 2000, Development, 127:4335).
Neublastin is a member of the glial cell line-derived neurotrophic factor (GDNF) ligand family. GDNF ligands activate both Ras and phosphatidylinositol-3-kinase signal transduction pathways by engaging the membrane-bound c-RET receptor tyrosine kinase. This c-RET-mediated signaling requires an additional co-receptor, a glycosylphosphatidyl inositol (GPI)-anchored GDNF family receptor alpha (GFRalpha) protein, which confers ligand specificity to c-RET. Four GFRalpha co-receptor proteins have been identified (GFRalpha-4). Neublastin shows highest affinity for GFRalpha3 in vitro, however in studies using human fibroblasts, neublastin can stimulate c-RET-dependent signaling through either GFRalpha3 or GFRalpha1 (Baudet et al., 2000, Development, 127:4335; Masure et al., 1999, Eur. J. Biochem. 266:892; Rosenblad et al., 2000, Mol. Cell Neurosci., 15(2):199).
The neublastin/c-RET/GFRalpha3 ternary complex is localized predominantly to nociceptive sensory neurons that detect pain and injury (Orozco et al., 2001, Eur. J. Neurosci., 13(11):2177). Neublastin thus has potential clinical application in the treatment of neuropathy and more specifically in the treatment of neuropathic pain. In addition, neublastin and GFRalpha3/RET are expressed at enhanced levels in pancreatic cancer tissues and neublastin promotes pancreatic cancer cell invasion (Ceyhan et al., 2006, Annals of Surgery, 244:274).